The malaria parasite avidly consumes the host hemoglobin as a source of nutrients. Plasmepsin I and II are proteases from Plasimodium falciparum that are required for the initial stages of hemoglobin digestion. The primary site of hydrolysis is in the .alpha.-chain of hemoglobin between Phe 33 and Leu 34; however other sites are substrates as well. It has been shown that a peptidomimetic inhibitor blocked plasmepsin, thus preventing hemoglobin degradation and resulting in death of the malaria parasite in culture (Francis, S. E., Gluzman, I. Y., Oksman, A., Knickerbocker, A., Mueller, R., Bryant, M. L,., Sherman, D. R., Russell, D. G. and Goldberg, D. E. (1994) EMBO J. 13, 306-317). Due to the increasing problem of resistance to known antimalarial therapies, new antimalarial therapies are desperately needed. Therefore, plasmepsin inhibition is an excellent target for antimalarial therapy.
Cathepsin D is a human protease in the endosomal-lysosomal pathway involved in lysosomal biogenesis and protein targeting. Cathepsin D may also be involved in antigen processing and presentation of peptide fragments. Therefore, cathepsin D displays broad substrate specificity but prefers hydrophobic residues on either side of the scissile bond. Cathepsin D has been implicated in a variety of diseases such as connective tissue disease, muscular dystrophy and breast cancer. Most recently, cathepsin D is believed to be .gamma.-secretase, the protease which processes the .beta.-amyloid precursor protein to generate the C-terminus of .beta.-amyloid (Dreyer, R. N., Bausch, K. M., Fracasso, P., Hammond, L. J., Wunderlich, D., Wirak, D. O., Davis, G., Brini, C. M., Bucholz, T. M., Konig, G., Kamark, M. E., and Tamburini, P. P. (1994) Eur. J. Biochem., 224, 265-271 and Ladror, U. S., Synder, S. W., Wang, G. T., Holzman, T. F., and Krafft, G. A. (1994) J. Biol. Chem., 269, 18422-18428). .beta.-Amyloid is the major component of plaques in the brains of Alzheimer's patients. Therefore, inhibitors of cathepsin D could be useful in treating various human diseases.
The present invention relates to hydroxypropyl amides and their inhibiting action against aspartyl proteases. In particular, the invention relates to the identification of inhibitors that display selective inhibitory activity against plasmepsin and cathepsin D. Although statine-containing peptides are known to inhibit aspartyl proteases (Shewale, J. G.; Takahashi, R.; Tang, J.; Aspartic Proteinases and Their Inhibitors, Kostka, V., Ed. Walter de Gruyter: Berlin, 1986; pp 101-116), few potent and selective inhibitors are known for plasmepsin (U.S. Pat. No. 5,734,054). The invention also relates to the solid phase synthesis of such agents.